REVIEW URRENT C OPINION
Chronic pancreatitis Anand R. Gupte a,b and Chris E. Forsmark a
Purpose of review We review selected important clinical observations in chronic pancreatitis reported in 2013. Recent findings Early diagnosis of chronic pancreatitis remains difficult, although newer techniques utilizing endoscopic ultrasonography-elastography and MRI hold promise. Patients with chronic pancreatitis are at risk of nutritional deficiencies. Osteoporosis, osteopenia, and bone fracture are particularly common in these patients, and require active intervention and treatment. Diabetes caused by chronic pancreatitis, type 3c diabetes, has specific characteristics and requires careful management. Antioxidants and neuromodulators may decrease pain in some patients with chronic pancreatitis. Endoscopic treatment is effective and can be utilized in patients with painful chronic pancreatitis, although randomized trials demonstrate that surgical therapy is somewhat more durable and effective. Although surgery has typically been a last resort, some advocate early surgical intervention but the optimal time remains unknown. Summary Early diagnosis of pancreatitis may be improved by newer techniques associated with endoscopic ultrasonography imaging. Treatment of nutritional deficiencies and diabetes is an important aspect of treating chronic pancreatitis. Pain relief with adjunct means of pain modulation should be tried before starting narcotics for pain control. Endoscopic therapy is appropriate for treating chronic pancreatitis and its local complications and surgical intervention can be considered early in carefully selected individuals. Keywords chronic pancreatitis, lithotripsy, nutrition, pain
INTRODUCTION Chronic pancreatitis is a progressive fibro-inflammatory syndrome caused by a variety of etiological factors. The condition is associated with numerous genetic mutations and polymorphisms that predispose to disease, with varied environmental disease triggers, which are together necessary for disease expression. Histologically, it is characterized by mononuclear cell infiltration and the activation of pancreatic stellate cells with subsequent fibrosis and acinar and islet cell loss. The management of this condition is challenging, and most patients remain symptomatic and suffer from complications despite medical, endoscopic, and surgical therapy. Accurate diagnosis of chronic pancreatitis in the early stages when therapy might be most effective remains difficult. In this review, we focus on recent publications that address issues including early and accurate diagnosis, the role of genetics and environmental toxins, natural history of disease progression, mechanisms of pain, nutritional and metabolic issues associated with chronic pancreatitis, and recent developments in the management of www.co-gastroenterology.com
the major features of exocrine insufficiency, endocrine insufficiency, and abdominal pain.
DIAGNOSIS OF CHRONIC PANCREATITIS In advanced or longstanding chronic pancreatitis, the diagnosis is usually easy to establish with crosssectional imaging [e.g., computed tomography (CT)], although differentiating chronic pancreatitis from pancreatic malignancy may be difficult. Diagnosis in earlier stages is often difficult and has relied on endoscopic ultrasonography (EUS) or pancreatic function testing (PFT). The main agent for PFT, a Division of Gastroenterology, Hepatology and Nutrition, University of Florida and bDivision of Gastroenterology, Malcolm Randall VA Medical Center, Gainesville, Florida, USA
Correspondence to Chris E. Forsmark, MD, Division of Gastroenterology, Hepatology and Nutrition, University of Florida, Box 100214, 1600 SW Archer Road, Gainesville, FL 32610, USA. Tel: +1 352 273 9472; fax: +1 352 627 9002; e-mail: [email protected] Curr Opin Gastroenterol 2014, 30:500–505 DOI:10.1097/MOG.0000000000000094 Volume 30 Number 5 September 2014
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Chronic pancreatitis Gupte and Forsmark
KEY POINTS Newer techniques, such as spin labeling and contrastenhanced elastography associated with EUS imaging, may help in early diagnosis of chronic pancreatitis. Identification and treatment of nutritional deficiencies and diabetes are an important aspect of managing patients with chronic pancreatitis. Adjunct means of pain modulation, such as use of antioxidants, antidepressants, and nonnarcotic agents as well as avoidance of smoking and alcohol, should be tried before starting narcotics for pain control. Endoscopic therapy is appropriate for initial treatment of chronic pancreatitis and its local complications but surgical intervention can be considered early in carefully selected individuals.
provided objective information to complement the more qualitative EUS image criteria [5]. Elastography, such as EUS imaging features, is also affected by age [6] in that aging produces a stiffer pancreas at elastography, a key diagnostic feature of chronic pancreatitis. Contrast-enhancing low mechanical index (CELMI) and high mechanical index techniques (CEHMI) have also become available for EUS. Hocke et al. [7] compared elastography with CEHMI-EUS and CELMI-EUS in discriminating focal chronic pancreatitis and pancreatic cancer and found CEHMI-EUS to be more reliable. Similar efforts to improve the accuracy of MRI in early diagnosis and in differentiating chronic pancreatitis from pancreatic cancer include the use of secretin infusions to estimate pancreatic function and techniques including spectroscopy, spin labeling [8 ], and quantitative assessment of individual MRI features. Despite these advances, the ability to diagnose early chronic pancreatitis by either EUS or MRI remains plagued by high rates of both false positive and false negative results [9,10]. Direct PFT, using secretin, can be performed with either a Dreiling tube or an endoscope. A recent retrospective analysis of 20 patients with an abnormal pancreatic function test but no other imaging evidence of chronic pancreatitis who were followed for 1–11 years noted that 45% ultimately developed obvious chronic pancreatitis, compared with 3% of 70 patients with an initial normal function test [11]. Although direct pancreatic function tests appear to be very good at ruling out chronic pancreatitis in patients with possible early chronic pancreatitis, there are a substantial number of false positive results. Direct pancreatic function tests such as the secretin test are being used less with the more widespread availability of modern imaging techniques such as CT, MRI, and EUS [12]. &
secretin, has been unavailable in the United States for more than a year and has only recently again become available for use. PFT is still only performed at a few centers in the United States, although data support it as the most sensitive test for early diagnosis. EUS has been shown to be more sensitive than cross-sectional imaging and is commonly used for diagnosis, and particularly for early diagnosis of chronic pancreatitis. A new scoring system for EUS diagnosis of chronic pancreatitis, the Rosemont criteria, is used by some but does not appear to be any more accurate, reproducible, or precise than previous nomenclature using minimal standard terminology [1]. A recent study noted that many EUS reports do not even specify the nine separate minimal standard terminology criteria in patients with suspected chronic pancreatitis, averaging only five [2], suggesting a need for quality improvement in EUS reports. A challenge in the use of EUS for early diagnosis of chronic pancreatitis has been the realization that similar endosonographic changes within the pancreas can be appreciated in patients who are elderly, who smoke or drink alcohol, who have diabetes or chronic renal failure, and who have had a recent episode of acute pancreatitis. Attempts to improve EUS diagnosis include the use of contrast-enhanced EUS [3] and computer aided image analysis [4] to differentiate chronic pancreatitis from pancreatic malignancy. Recently, Iglesias˜oz [5] concluded that Garcia and Domı´nguez-Mun quantitative elastography performed during EUS can aid in diagnosing pancreatitis in the nonadvanced stage. They evaluated 191 patients prospectively and found that the accuracy of quantitative EUS-elastography was highly correlated with EUS imaging evidence of chronic pancreatitis and
NUTRITION IN CHRONIC PANCREATITIS Exocrine insufficiency may develop in longstanding chronic pancreatitis, leading to malnutrition. Malnutrition may result from maldigestion (lack of pancreatic enzymes), inadequate intake of nutrients (due to alcoholism or pain), or increased metabolic activity due to severity of disease. Recent reviews [10,13] emphasize the need to develop good nutritional practices by screening chronic pancreatitis patients at risk for malnutrition, performing a thorough nutritional assessment, developing a nutrition plan including abstinence from alcohol and tobacco, treating pain, and initiating dietary modifications and pancreatic enzyme replacement therapy (PERT). There has been a major change in PERT therapy in that only brand-name agents are
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now available [10]. Appropriate therapy should start with at least 40 000–50 000 USP units of lipase with each meal, although many patients require twice this amount. Although deficiencies of vitamin A, D, E, and K are well documented in chronic pancreatitis and correlate with severity of steatorrhea, deficiencies of vitamin B12, zinc, calcium, magnesium, thiamine, and folic acid have also been seen. These deficiencies are seen even in patients who appear to be well nourished or are obese [14 ]. Frequent small meals, limiting carbohydrate intake (especially in patients with diabetes mellitus), a protein intake of 1.0–1.5 g/kg body weight, and about 30–40% of calories coming from fat is suggested and usually well tolerated. Bone mineral density (BMD) testing is also appropriate when treating patients with chronic pancreatitis and exocrine insufficiency, and a baseline evaluation of nutritional status (weight, BMI, complete blood count, basic metabolic profile, albumin, prealbumin, INR, carotene, and vitamin D) should be performed before starting treatment with pancreatic enzyme replacement therapy [10]. A prospective study conducted by Sikkens et al. [15] found that deficiencies of fatsoluble vitamin and a decreased BMD are frequently present in chronic pancreatitis patients including those that were exocrine sufficient. Consequently, all patients with chronic pancreatitis should be routinely screened for fat-soluble vitamin deficiencies and a decreased BMD. Osteoporosis and osteopenia are very common in patients with chronic pancreatitis; a recent review and meta-analysis from Duggan et al. [16] reports 25% of patients have osteoporosis and an additional 40% have osteopenia. A population-based analysis from the Netherlands noted a dramatic increase in fracture risk in patients with chronic pancreatitis with a HR of 1.7, and the risk was particularly increased in younger patients and was lowered in those being treated with PERT [17]. &&
DIABETES IN CHRONIC PANCREATITIS Diabetes due to the destruction of islets in patients with chronic pancreatitis is termed type 3c diabetes [18 ]. This produces a complex diabetic condition, especially in patients with underlying exocrine insufficiency, maldigestion, and malnutrition. Treatment-induced hypoglycemia is common. In a recent consensus report, routine testing of fasting glucose and HbA1c should be performed in patients with chronic pancreatitis [19]. In addition, an absent pancreatic polypeptide response can be used as a specific indicator of type 3c diabetes. Treatment requires PERT [20] to maximize incretin secretion and nutritional status, in addition to diabetic medications, and early referral to an endocrine specialist for this brittle &
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form of diabetes. Although chronic pancreatitis is a risk factor for pancreatic ductal carcinoma [20], the presence of diabetes serves as an additional risk factor in these patients with chronic pancreatitis.
GENETICS AND CHRONIC PANCREATITIS The genetic predisposition to chronic pancreatitis is complex. In addition to the now well established roles of PRSS1, cystic fibrosis transmembrane conductance regulator (CFTR), chymotrypsin C (CTRC), and serine protease inhibitor kazal-type 1 (SPINK-1), a number of important new polymorphisms have been identified. Polymorphisms in the tight junction protein Claudin-2, an x-linked gene [21], work synergistically with alcohol and may explain the dramatic increase in risk for men to develop alcohol-induced pancreatitis. Polymorphisms in CPA1, encoding a carboxypeptidase, were recently found to be strongly associated with early onset chronic pancreatitis [22]. CTRC polymorphisms have now been shown to play a role in tropical pancreatitis [23] along with mutations in SPINK-1. The mechanisms of CTRC loss of function, which produces the increased risk of chronic pancreatitis, have recently been elucidated [24]. Finally, exonic and intronic variants that are not generally tested for add to the genetic risks of chronic pancreatitis. Genetic testing is evolving, but at the current time these new insights have not translated into recommendations for routine genetic testing of patients with chronic pancreatitis.
AUTOIMMUNE PANCREATITIS Autoimmune pancreatitis comprises two variants. Type 1 is a systemic disease affecting pancreas, bile ducts, kidneys, salivary glands, retroperitoneum, and other organs. It is associated with elevations in serum levels of IgG4, and with infiltration of these affected organs by IgG4-bearing plasma cells. Type 2 affects only the pancreas, and is not associated with IgG4. Both types are steroid responsive, but relapses in Type 1 are common. Relapses generally require the use of immunosuppressives such as azathioprine [25], with agents such as rituximab used for failures of azathioprine [26]. The long-term outcome of this condition is not known, but exocrine and endocrine insufficiency can occur although pancreatic ductal stones and malignancy appear to be rare [27].
MANAGEMENT OF PAIN Pain in chronic pancreatitis is multifactorial with inflammatory and neuropathic components. Abnormalities in peripheral and central pain processing are Volume 30 Number 5 September 2014
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commonly identified [28–31] and these processes produce a sensitized pain state, in which therapy directed at the pancreas or pancreatic duct is often ineffective. A recent study from Bahuva et al. [32] documented again that the appearance of the pancreas on cross-sectional imaging and the severity of pain are often discordant, supporting the role of central mechanisms of pain in these patients. A similar study from Frokjaer et al. [33 ] confirmed these findings. Medical treatment options for painful chronic pancreatitis include avoidance of alcohol and smoking, pancreatic enzymes, pain medications, antioxidants, and adjunctive agents [10]. Pain management in the early stages may respond to nonnarcotic analgesics, but if the pain becomes more constant or debilitating, introduction of narcotic analgesics is appropriate [34]. Addiction and the abuse of narcotics do occur in these patients, and are particularly significant in patients with depression, higher pain intensity, and alcohol use [35]. Recent studies are mixed on the effect of antioxidants [10,36,37], but these agents may be effective in a subset of patients with preexisting nutritional deficiencies. One randomized study did document a modest effect of pregabalin as an adjunctive agent with narcotics [38]. Studies have not been performed on tricyclic antidepressants or selective serotonin reuptake inhibitor/norepinephrine and selective serotonin reuptake inhibitor agents, but they are commonly used as adjunctive agents as well [10]. If conservative medical treatment does not succeed, endoscopic treatment is pursued if the ductal anatomy is appropriate (i.e., a dilated main pancreatic duct with obstructing stone or stricture). He et al. [39 ] showed that use of the M-ANNHEIM classification system for chronic pancreatitis could improve time to diagnosis, allowing more time for early endoscopic intervention and improvement in pain relief and patient outcomes. Not all patients benefit from endoscopic therapy. In two randomized trials and in a systematic review published by D’Haese et al. [40], surgical treatment was seen to have better outcomes and is more long lasting compared with endoscopic intervention. Many patients still choose endoscopic therapy first, over a desire to avoid surgery. Endoscopic therapy, if undertaken, involves stenting of strictures and removal of pancreatic ductal stones. These stones are difficult to remove without extracorporeal or intraductal lithotripsy [41]. Long-term data on the use of lithotripsy were reported by Tandan et al. [42], who followed a large cohort (636) of patients with idiopathic (tropical) calcific pancreatitis who underwent extracorporeal shock wave lithotripsy (ESWL) followed by endoscopic retrograde cholangiopancreatography &
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(ERCP). Absence of pain was seen in 60% of patients in long-term (up to 96 months) followup. Recurrence of calculi was seen in 22%. Quality of life improved substantially. The authors thus concluded that ESWL for large pancreatic duct calculi offers good results in patients with idiopathic calcific chronic pancreatitis on long-term followup [42]. Patients with a small pancreatic duct or diffuse punctate stones are not amenable to ESWL. Surgical therapy is usually recommended in patients who do not respond to medical or endoscopic therapy, those who have local complications such as biliary or duodenal obstruction, and in patients in whom malignancy cannot be excluded [10]. The optimal surgical procedure should manage pain, reduce opioid use, preserve as much as possible pancreatic exocrine and endocrine function, resolve local complications, and improve the quality of life [43 ]. Surgical approaches include lateral pancreaticojejunostomy or the modified Puestow procedure, the duodenum preserving pancreatic head resection procedures (Frey, Beger, or Berne) or the Whipple procedure. Bachmann and Tomkoetter [44] performed a randomized controlled trial comparing extended drainage procedure (Frey) with standard pylorus preserving pancreatoduodenectomy and found that organ-sparing procedure (Frey) showed better short-term results and a longer survival. Similarly, a study by Sudo et al. [45] from Japan showed that full-length lateral pancreaticojejunostomy was well tolerated, feasible, and effective for managing chronic pancreatitis. Thus organ-preserving surgery is preferred. After surgery, insulin independence and the use of PERT are associated with lower mortality [46]. Total pancreatectomy is rarely used for the treatment of chronic pancreatitis and is reserved for patients who failed previous surgical interventions, have severe pain with complete exocrine and endocrine pancreatic failure or as prophylactic procedure for pancreatic cancer in patients with hereditary pancreatitis or familial pancreatic cancer [43 ]. In recent years total pancreatectomy with islet cell autotransplantation (IAT) has been performed in patients with chronic pancreatitis. As patients get their own islet cells, it obviates the need for immunosuppressive therapy. Garcea et al. [47] observed that total pancreatectomy with IAT reduced pain, lowered insulin requirements, and conferred a surgical advantage over total pancreatectomy alone. TP-IAT is being utilized more frequently and at earlier stages of disease [48], although this approach is controversial. A recent systematic review noted reasonable pain relief in patients undergoing TP-IAT, with insulin independence of 46% at 5 years and 10% at 8 years after surgery [49].
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The optimal timing for surgical intervention in chronic pancreatitis is still debatable. Some advocate early surgery prior to the time that narcotic dependence develops. An open-label randomized controlled multicenter superiority trial by a Dutch group, the ESCAPE (Early Surgery versus Optimal Current Step-Up Practice for Chronic Pancreatitis trial) trial aims to compare early surgery versus the current step up treatment strategy in patients with chronic pancreatitis with dilated pancreatoduodenectomy and pain [50]. This trial may help to decide if early surgical intervention would lead to better long-term pain control and pancreatic function.
ENDOSCOPIC MANAGEMENT OF CHRONIC PANCREATITIS ASSOCIATED BILE DUCT STRICTURE OR PSEUDOCYST Endoscopic management of chronic pancreatitis is aimed at decreasing pain and treating associated complications, such as strictures (biliary and pancreatic), ductal leaks, intraductal calculi, or pseudocysts. Chronic pancreatitis related biliary strictures occur because of progressive fibrosis of pancreatic parenchyma and are more resistant to endoscopic dilation than other benign biliary strictures [51]. Wagh et al. [52] prospectively evaluated the efficacy of fully covered self-expandable metal stents as an alternative to plastic stenting in patients with biliary strictures, including those due to chronic pancreatitis. Short-term stricture resolution was seen in 96% of the patients, long-term success was seen in 83% of the patients. All of the failures were seen in patients with biliary strictures in the setting of chronic calcific pancreatitis. Similar findings were reported by Irani et al. [53]. These data underscore the recalcitrant nature of chronic pancreatitis associated biliary strictures, and imply that surgical biliary bypass is often preferable. Stenting is initially recommended in patients who present with jaundice or cholangitis as well as in patients unfit for surgery, or those who refuse surgery. Use of fully covered self-expandable metal stents by virtue of their larger diameter, better biliary drainage, and longer patency is a feasible alternative in treatment of common bile duct strictures related to chronic pancreatitis in nonsurgical patients [51]. Pseudocysts can be managed with endoscopic, surgical, or percutaneous methods. A recent randomized trial by Varadarajulu et al. noted similar efficacy and less cost for endoscopic drainage compared with surgical cystgastrostomy [54,55]. This trial suggests that endoscopic therapy should be the first-line treatment at centers with appropriate endoscopic expertise in EUS-guided drainage. 504
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CONCLUSION Literature from this year emphasized early diagnosis and intervention in treating patients with chronic pancreatitis. Patients with chronic pancreatitis are at risk of several nutrient deficiencies, which should be recognized and treated to improve outcomes. New guidelines for the diagnosis and management of pancreatogenic diabetes were published. Adjunctive treatments play a role in treatment of pain. Endoscopic treatment along with lithotripsy can be considered as an alternative to surgery in selected patients. Surgery is effective for treatment of pain and some complications, but endoscopic therapies are preferred for management of pseudocysts. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Stevens T, Lopez R, Adler DG, et al. Multicenter comparison of the interobserver agreement of standard EUS scoring and Rosemont classification scoring for diagnosis of chronic pancreatitis. Gastrointest Endosc 2010; 71:519–526. 2. Gardner TB, Taylor DJ, Gordon SR. Reported findings on endoscopic ultrasound examinations for chronic pancreatitis: toward establishing an endoscopic ultrasound quality benchmark. Pancreas 2014; 43:37–40. 3. Gheonea DI, Streba CT, Ciurea T, Saftoiu A. Quantitative low mechanical index contrast-enhanced endoscopic ultrasound for the differential diagnosis of pseudotumoral chronic pancreatitis and pancreatic cancer. BMC Gastroenterol 2013; 13:2. 4. Zhu M, Xu C, Wu Y, et al. Differentiation of pancreatic cancer and chronic pancreatitis using computer-aided diagnosis of endoscopic ultrasound (EUS) images: a diagnostic test. PLoS One 2013; 8:e63820. 5. Iglesias-Garcia J, Domı´nguez-Mun˜oz JE. Quantitative elastography associated with endoscopic ultrasound for the diagnosis of chronic pancreatitis. Endoscopy 2013; 45:781–788. 6. Janssen J, Papavassiliou I. Effect of aging and diffuse chronic pancreatitis on pancreas elasticity evaluated using semiquantitative EUS elastography. Ultraschall Med 2014; 35:253–258. 7. Hocke M, Ignee A, Dietrich CA. Advanced endosonographic diagnostic tools for discrimination of focal chronic pancreatitis and pancreatic carcinoma– elastography, contrast enhanced high mechanical index (CEHMI) and low mechanical index (CELMI) endosonography in direct comparison. Z Gastroenterol 2012; 50:199–203. 8. Sugita R, Furuta A, Yamakazi T, et al. Direct visualization of pancreatic juice & flow using unenhanced MRI with spin labeling can be an aid in diagnosing chronic pancreatitis. AJR Am J Ropentgenol 2014; 202:1027–1034. Spin labeling, a new technique, allows direct pancreatic juice visualization. 9. Cote GA, Smith J, Sherman S, Kelly K. Technologies for imaging the normal and diseased pancreas. Gastroenterology 2013; 144:1262–1271. 10. Forsmark CE. Management of chronic pancreatitis. Gastroenterology 2013; 144:1282–1291. 11. Ketwaroo G, Brown A, Young B, et al. Defining the accuracy of secretin pancreatic function testing in patients with suspected early chronic pancreatitis. Am J Gastroenterol 2013; 108:1360–1366. 12. Liao Z, Jin G, Cai D, et al. Guidelines: diagnosis and therapy for chronic pancreatitis. J Interv Gastroenterol 2013; 3:133–136. 13. Rasmussen HH, Irtun O, Olesen SS, et al. Nutrition in chronic pancreatitis. World J Gastroenterol 2013; 19:7267–7275.
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Chronic pancreatitis Gupte and Forsmark 14. Duggan SN, Smyth ND, O’Sullivan M, et al. The prevalence of malnutrition and fat-soluble vitamin deficiencies in chronic pancreatitis. Nutr Clin Pract 2014; 29:348–354. In chronic pancreatitis, malabsorption, pain and poor diet place patients at risk of malnutrition. In a prospective controlled cohort study, patients with chronic pancreatitis were noted to have lower muscle stores, strength, and abnormal vitamin levels. This highlights the importance to perform anthropometry and vitamin status assessment in patients with chronic pancreatitis. 15. Sikkens EC, Cahen DL, Koch AD, et al. The prevalence of fat-soluble vitamin deficiencies and a decreased bone mass in patients with chronic pancreatitis. Pancreatology 2013; 13:238–242. 16. Duggan SN, Smyth ND, Murphy A, et al. High prevalence of osteoporosis in patients with chronic pancreatitis: a systematic review and meta-analysis. Clin Gast Hepatol 2014; 12:219–228. 17. Bang UC, Benefield T, Bendtsen F, et al. The risk of fracture among patients with cirrhosis or chronic pancreatitis. Clin Gast Hepatol 2014; 12:320– 326. 18. Ewald N, Hardt PD. Diagnosis and treatment of diabetes mellitus in chronic & pancreatitis. World J Gastroenterol 2013; 19:7276–7281. The prevalence and importance of pancreatogenic diabetes are underestimated, and chronic pancreatitis as a potential cause of type 3 diabetes mellitus is underappreciated. In such patients, treating with appropriate enzyme replacement, preventing and treating fat-soluble vitamin deficiency, restoring fat hydrolysis, and incretin secretions are important considerations of medical therapy. 19. Rickels MR, Bellin M, Toledo FG, et al. Detection, evaluation and treatment of diabetes mellitus in chronic pancreatitis: recommendations from PancreasFest. Pancreatology 2013; 13:336–342. 20. Andersen DK, Andren-Sandberg A, Duell EJ, et al. Pancreatitis-diabetespancreatic cancer: summary of an NIDDK-NCI workshop. Pancreas 2013; 42:1227–1237. 21. Whitcomb DC. Genetic risk factors for pancreatic disorders. Gastroenterology 2013; 144:1292–1302. 22. Witt H, Beer S, Rosendahl J, et al. Variants in CPA1 are strongly associated with early onset chronic pancreatitis. Nat Genet 2013; 45:1216–1220. 23. Paliwal S, Bhaskar S, Mani KR, et al. Comprehensive screening of chymotrypsin C (CTRC) gene in tropical calcific pancreatitis identifies novel variants. Gut 2013; 62:1602–1606. 24. Beer S, Zhou J, Szabo A, et al. Comprehensive functional analysis of chymotrypsin C (CTRC) variants reveals distinct loss-of-function mechanisms associated with pancreatitis risk. Gut 2013; 62:1616–1624. 25. Kamisawa T, Chari ST, Lerch MM, et al. Recent advances in autoimmune pancreatitis: type 1 and type 2. Gut 2013; 62:1373–1380. 26. Hart PA, Topazian MD, Witzig TE, et al. Treatment of relapsing autoimmune pancreatitis with immunomodulators and rituximab: the Mayo experience. Gut 2013; 62:1607–1615. 27. Hart PA, Kamisawa T, Brugge WR, et al. Long-term outcomes of autoimmune pancreatitis: a multicenter, international analysis. Gut 2013; 62:1771–1776. 28. De Vries M, Wilder-Smith OH, Jongsma ML, et al. Altered resting state EEG in chronic pancreatitis patients: towards a marker for chronic pain. J Pain Res 2013; 25:815–824. 29. Bouwense SA, Ahmed Ali U, ten Broek RP, et al. Altered central pain processing after pancreatic surgery for chronic pancreatitis. Br J Surg 2013; 100:1797–1804. 30. Bouwense SA, Olesen SS, Drewes AM, et al. Is altered central pain processing related to disease stage in chronic pancreatitis patients with pain? An exploratory study. PLoS One 2013; 8:e55460. 31. Poulsen JL, Olesen SS, Malver LP, et al. Pain and chronic pancreatitis: a complex interplay of multiple mechanisms. World J Gastroenterol 2013; 19:7282–7291. 32. Bahuva R, Walsh RM, Kapural L, Stevens T. Morphologic abnormalities are poorly predictive of visceral pain in chronic pancreatitis. Pancreas 2013; 42:6–10. 33. Frokjaer JB, Olesen SS, Drewes AM. Fibrosis, atrophy, and ductal pathology & in chronic pancreatitis are associated with pancreatic function but independent of symptoms. Pancreas 2013; 42:1182–1187. In this Danish study, MRCP with diffusion weighted imaging was performed in patients with chronic pancreatitis and controls. Fibrosis, atrophy, and ductal pathology was noted in patients with chronic pancreatitis and these in turn were associated with Vit D, phosphate, hemoglobin, and glycated hemoglobin levels. However symptomatic chronic pancreatitis was noted to have a more complex pathophysiology independent of imaging pathology. 34. Enweluzo C, Tlhabano L. Pain management in chronic pancreatitis: taming the beast. Clin Exp Gastroenterol 2013; 6:167–171.
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35. Barth KS, Balliet W, P:elic CM, et al. Screening for current opiod misuse and associated risk factors among patients with chronic nonalcoholic pancreatitis pain. Pain MedD 2014 ; Doi: 10.1111/pme/12403 [Epub ahead of print] 36. Forsmark CE, Liddle RA. The challenging task of treating painful chronic pancreatitis. Gastroenterology 2012; 143:533–535. 37. Cai GH, Huang J, Zhao Y, et al. Antioxidant therapy for pain relief in patients with chronic pancreatitis: a systematic review and meta-analysis. Pain Physician 2013; 16:521–532. 38. Olesen SS, Bouwense SA, Wilder-Smith OH, et al. Pregabalin reduces pain in patients with chronic pancreatitis I a randomized, controlled trial. Gastroenterology 2011; 141:536–543. 39. He YX1, Xu HW, Sun XT, et al. Endoscopic management of early-stage & chronic pancreatitis based on M-ANNHEIM classification system: a prospective study. Pancreas 2014. [Epub ahead of print] M-ANNHEIM classification system was used to categorize patients with chronic pancreatitis. Patients receiving endoscopic treatment at early stage (1A) had more improvement in pain scores than those receiving treatment at later stages. Patients with stage 1A also had a higher incidence of post ERCP pancreatitis thus highlighting the importance of careful patient selection before undergoing therapeutic endoscopy. 40. D’Haese JG, Ceyhan GO, Demir IE, et al. Treatment options in painful chronic pancreatitis: a systematic review. HPB (Oxford) 2014; 16:512–521. 41. Kozarek R. Recent research on extracorporeal shock wave lithotripsy with ERCP for treatment of chronic calcific pancreatitis. Gastroenterol Hepatol (NY) 2012; 8:478–481. 42. Tandan M, Reddy DN, Talukdar R. Long-term clinical outcomes of extracorporeal shockwave lithotripsy in painful chronic calcific pancreatitis. Gastrointest Endosc 2013; 78:726–733. 43. Issa Y1, van Santvoort HC, van Goor H, et al. Surgical and endoscopic && treatment of pain in chronic pancreatitis: A multidisciplinary update. Dig Surg 2013; 30:35–50. Treatment of pain in chronic pancreatitis is challenging and evidence-based protocols are lacking. A plethora of medical, endoscopic, and surgical options are available but treatment needs to be individualized. This review highlights stepby-step approach toward treatment of pain in chronic pancreatitis with emphasis on ductal drainage and timing of surgical intervention. 44. Bachmann K, Tomkoetter L. Is the Whipple procedure harmful for long-term outcome in treatment of chronic pancreatitis? 15-years follow-up comparing the outcome after pylorus-preserving pancreatoduodenectomy and Frey procedure in chronic pancreatitis. Ann Surg 2013; 258:815–820. 45. Sudo T, Murakami Y, Uemura K, et al. Short- and long-term results of lateral pancreaticojejunostomy for chronic pancreatitis: a retrospective Japanese single-center study. J Hepatobiliary Pancreat Sci 2014; 21:426–432. 46. Winny M, Paroglou V, Bektas H, et al. Insulin independence and pancreatic enzyme replacement therapy are independent prognostic factors for long-term survival after operation for chronic pancreatitis. Surgery 2014; 155:271–279. 47. Garcea G, Pollard CA, Illouz S, et al. Patient satisfaction and cost-effectiveness following total pancreatectomy with islet cell transplantation for chronic pancreatic. Pancreas 2013; 42:322–328. 48. Bellin MD, Freeman ML, Gelrud A, et al. Total pancreatectomy and islet autotransplantation in chronic pancreatitis: recommendations from PancreasFest. Pancreatology 2014; 14:27–35. 49. Bramis K, Gordon-Weeks AN, Friend PJ, et al. Systematic review of total pancreatectomy and islet autotransplantation for chronic pancreatitis. Br J Surg 2012; 99:761–766. 50. Ahmed Ali U, Issa Y, Bruno MJ, et al. Early surgery versus optimal current stepup practice for chronic pancreatitis (ESCAPE): design and rationale of a randomized trial. BMC Gastroenterol 2013; 13:49. 51. Familiari P, Bosˇkoski I, Bove V, Costamagna G. ERCP for biliary strictures associated with chronic pancreatitis. Gastrointest Endosc Clin N Am 2013; 23:833–845. 52. Wagh MS, Chavalitdhamrong D, Moezardalan K, et al. Effectiveness and safety of endoscopic treatment of benign biliary strictures using a new fully covered self-expandable metal stent. Diagn Ther Endosc 2013; 183513. Doi: 10.1155/2013/183513. [Epub ahead of print] 53. Irani S, Baron TH, Akbar A, et al. Endoscopic treatment of benign biliary strictures using covered self-expandable metal stents (CSEMS). Dig Dis Sci 2014; 59:152–160. 54. Varadarajulu S, Bang JY, Sutton BS, et al. Equal efficacy of endoscopic and surgical cystgastrostomy for pancreatic pseudocyst drainage in a randomized trial. Gastroenterology 2013; 145:583–590. 55. Chauhan SS, Forsmark CE. Evidence-based treatment of pancreatic pseudocysts. Gastroenterology 2013; 145:511–513.
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Chronic pancreatitis Anand R. Gupte a,b and Chris E. Forsmark a
Purpose of review We review selected important clinical observations in chronic pancreatitis reported in 2013. Recent findings Early diagnosis of chronic pancreatitis remains difficult, although newer techniques utilizing endoscopic ultrasonography-elastography and MRI hold promise. Patients with chronic pancreatitis are at risk of nutritional deficiencies. Osteoporosis, osteopenia, and bone fracture are particularly common in these patients, and require active intervention and treatment. Diabetes caused by chronic pancreatitis, type 3c diabetes, has specific characteristics and requires careful management. Antioxidants and neuromodulators may decrease pain in some patients with chronic pancreatitis. Endoscopic treatment is effective and can be utilized in patients with painful chronic pancreatitis, although randomized trials demonstrate that surgical therapy is somewhat more durable and effective. Although surgery has typically been a last resort, some advocate early surgical intervention but the optimal time remains unknown. Summary Early diagnosis of pancreatitis may be improved by newer techniques associated with endoscopic ultrasonography imaging. Treatment of nutritional deficiencies and diabetes is an important aspect of treating chronic pancreatitis. Pain relief with adjunct means of pain modulation should be tried before starting narcotics for pain control. Endoscopic therapy is appropriate for treating chronic pancreatitis and its local complications and surgical intervention can be considered early in carefully selected individuals. Keywords chronic pancreatitis, lithotripsy, nutrition, pain
INTRODUCTION Chronic pancreatitis is a progressive fibro-inflammatory syndrome caused by a variety of etiological factors. The condition is associated with numerous genetic mutations and polymorphisms that predispose to disease, with varied environmental disease triggers, which are together necessary for disease expression. Histologically, it is characterized by mononuclear cell infiltration and the activation of pancreatic stellate cells with subsequent fibrosis and acinar and islet cell loss. The management of this condition is challenging, and most patients remain symptomatic and suffer from complications despite medical, endoscopic, and surgical therapy. Accurate diagnosis of chronic pancreatitis in the early stages when therapy might be most effective remains difficult. In this review, we focus on recent publications that address issues including early and accurate diagnosis, the role of genetics and environmental toxins, natural history of disease progression, mechanisms of pain, nutritional and metabolic issues associated with chronic pancreatitis, and recent developments in the management of www.co-gastroenterology.com
the major features of exocrine insufficiency, endocrine insufficiency, and abdominal pain.
DIAGNOSIS OF CHRONIC PANCREATITIS In advanced or longstanding chronic pancreatitis, the diagnosis is usually easy to establish with crosssectional imaging [e.g., computed tomography (CT)], although differentiating chronic pancreatitis from pancreatic malignancy may be difficult. Diagnosis in earlier stages is often difficult and has relied on endoscopic ultrasonography (EUS) or pancreatic function testing (PFT). The main agent for PFT, a Division of Gastroenterology, Hepatology and Nutrition, University of Florida and bDivision of Gastroenterology, Malcolm Randall VA Medical Center, Gainesville, Florida, USA
Correspondence to Chris E. Forsmark, MD, Division of Gastroenterology, Hepatology and Nutrition, University of Florida, Box 100214, 1600 SW Archer Road, Gainesville, FL 32610, USA. Tel: +1 352 273 9472; fax: +1 352 627 9002; e-mail: [email protected] Curr Opin Gastroenterol 2014, 30:500–505 DOI:10.1097/MOG.0000000000000094 Volume 30 Number 5 September 2014
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Chronic pancreatitis Gupte and Forsmark
KEY POINTS Newer techniques, such as spin labeling and contrastenhanced elastography associated with EUS imaging, may help in early diagnosis of chronic pancreatitis. Identification and treatment of nutritional deficiencies and diabetes are an important aspect of managing patients with chronic pancreatitis. Adjunct means of pain modulation, such as use of antioxidants, antidepressants, and nonnarcotic agents as well as avoidance of smoking and alcohol, should be tried before starting narcotics for pain control. Endoscopic therapy is appropriate for initial treatment of chronic pancreatitis and its local complications but surgical intervention can be considered early in carefully selected individuals.
provided objective information to complement the more qualitative EUS image criteria [5]. Elastography, such as EUS imaging features, is also affected by age [6] in that aging produces a stiffer pancreas at elastography, a key diagnostic feature of chronic pancreatitis. Contrast-enhancing low mechanical index (CELMI) and high mechanical index techniques (CEHMI) have also become available for EUS. Hocke et al. [7] compared elastography with CEHMI-EUS and CELMI-EUS in discriminating focal chronic pancreatitis and pancreatic cancer and found CEHMI-EUS to be more reliable. Similar efforts to improve the accuracy of MRI in early diagnosis and in differentiating chronic pancreatitis from pancreatic cancer include the use of secretin infusions to estimate pancreatic function and techniques including spectroscopy, spin labeling [8 ], and quantitative assessment of individual MRI features. Despite these advances, the ability to diagnose early chronic pancreatitis by either EUS or MRI remains plagued by high rates of both false positive and false negative results [9,10]. Direct PFT, using secretin, can be performed with either a Dreiling tube or an endoscope. A recent retrospective analysis of 20 patients with an abnormal pancreatic function test but no other imaging evidence of chronic pancreatitis who were followed for 1–11 years noted that 45% ultimately developed obvious chronic pancreatitis, compared with 3% of 70 patients with an initial normal function test [11]. Although direct pancreatic function tests appear to be very good at ruling out chronic pancreatitis in patients with possible early chronic pancreatitis, there are a substantial number of false positive results. Direct pancreatic function tests such as the secretin test are being used less with the more widespread availability of modern imaging techniques such as CT, MRI, and EUS [12]. &
secretin, has been unavailable in the United States for more than a year and has only recently again become available for use. PFT is still only performed at a few centers in the United States, although data support it as the most sensitive test for early diagnosis. EUS has been shown to be more sensitive than cross-sectional imaging and is commonly used for diagnosis, and particularly for early diagnosis of chronic pancreatitis. A new scoring system for EUS diagnosis of chronic pancreatitis, the Rosemont criteria, is used by some but does not appear to be any more accurate, reproducible, or precise than previous nomenclature using minimal standard terminology [1]. A recent study noted that many EUS reports do not even specify the nine separate minimal standard terminology criteria in patients with suspected chronic pancreatitis, averaging only five [2], suggesting a need for quality improvement in EUS reports. A challenge in the use of EUS for early diagnosis of chronic pancreatitis has been the realization that similar endosonographic changes within the pancreas can be appreciated in patients who are elderly, who smoke or drink alcohol, who have diabetes or chronic renal failure, and who have had a recent episode of acute pancreatitis. Attempts to improve EUS diagnosis include the use of contrast-enhanced EUS [3] and computer aided image analysis [4] to differentiate chronic pancreatitis from pancreatic malignancy. Recently, Iglesias˜oz [5] concluded that Garcia and Domı´nguez-Mun quantitative elastography performed during EUS can aid in diagnosing pancreatitis in the nonadvanced stage. They evaluated 191 patients prospectively and found that the accuracy of quantitative EUS-elastography was highly correlated with EUS imaging evidence of chronic pancreatitis and
NUTRITION IN CHRONIC PANCREATITIS Exocrine insufficiency may develop in longstanding chronic pancreatitis, leading to malnutrition. Malnutrition may result from maldigestion (lack of pancreatic enzymes), inadequate intake of nutrients (due to alcoholism or pain), or increased metabolic activity due to severity of disease. Recent reviews [10,13] emphasize the need to develop good nutritional practices by screening chronic pancreatitis patients at risk for malnutrition, performing a thorough nutritional assessment, developing a nutrition plan including abstinence from alcohol and tobacco, treating pain, and initiating dietary modifications and pancreatic enzyme replacement therapy (PERT). There has been a major change in PERT therapy in that only brand-name agents are
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now available [10]. Appropriate therapy should start with at least 40 000–50 000 USP units of lipase with each meal, although many patients require twice this amount. Although deficiencies of vitamin A, D, E, and K are well documented in chronic pancreatitis and correlate with severity of steatorrhea, deficiencies of vitamin B12, zinc, calcium, magnesium, thiamine, and folic acid have also been seen. These deficiencies are seen even in patients who appear to be well nourished or are obese [14 ]. Frequent small meals, limiting carbohydrate intake (especially in patients with diabetes mellitus), a protein intake of 1.0–1.5 g/kg body weight, and about 30–40% of calories coming from fat is suggested and usually well tolerated. Bone mineral density (BMD) testing is also appropriate when treating patients with chronic pancreatitis and exocrine insufficiency, and a baseline evaluation of nutritional status (weight, BMI, complete blood count, basic metabolic profile, albumin, prealbumin, INR, carotene, and vitamin D) should be performed before starting treatment with pancreatic enzyme replacement therapy [10]. A prospective study conducted by Sikkens et al. [15] found that deficiencies of fatsoluble vitamin and a decreased BMD are frequently present in chronic pancreatitis patients including those that were exocrine sufficient. Consequently, all patients with chronic pancreatitis should be routinely screened for fat-soluble vitamin deficiencies and a decreased BMD. Osteoporosis and osteopenia are very common in patients with chronic pancreatitis; a recent review and meta-analysis from Duggan et al. [16] reports 25% of patients have osteoporosis and an additional 40% have osteopenia. A population-based analysis from the Netherlands noted a dramatic increase in fracture risk in patients with chronic pancreatitis with a HR of 1.7, and the risk was particularly increased in younger patients and was lowered in those being treated with PERT [17]. &&
DIABETES IN CHRONIC PANCREATITIS Diabetes due to the destruction of islets in patients with chronic pancreatitis is termed type 3c diabetes [18 ]. This produces a complex diabetic condition, especially in patients with underlying exocrine insufficiency, maldigestion, and malnutrition. Treatment-induced hypoglycemia is common. In a recent consensus report, routine testing of fasting glucose and HbA1c should be performed in patients with chronic pancreatitis [19]. In addition, an absent pancreatic polypeptide response can be used as a specific indicator of type 3c diabetes. Treatment requires PERT [20] to maximize incretin secretion and nutritional status, in addition to diabetic medications, and early referral to an endocrine specialist for this brittle &
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form of diabetes. Although chronic pancreatitis is a risk factor for pancreatic ductal carcinoma [20], the presence of diabetes serves as an additional risk factor in these patients with chronic pancreatitis.
GENETICS AND CHRONIC PANCREATITIS The genetic predisposition to chronic pancreatitis is complex. In addition to the now well established roles of PRSS1, cystic fibrosis transmembrane conductance regulator (CFTR), chymotrypsin C (CTRC), and serine protease inhibitor kazal-type 1 (SPINK-1), a number of important new polymorphisms have been identified. Polymorphisms in the tight junction protein Claudin-2, an x-linked gene [21], work synergistically with alcohol and may explain the dramatic increase in risk for men to develop alcohol-induced pancreatitis. Polymorphisms in CPA1, encoding a carboxypeptidase, were recently found to be strongly associated with early onset chronic pancreatitis [22]. CTRC polymorphisms have now been shown to play a role in tropical pancreatitis [23] along with mutations in SPINK-1. The mechanisms of CTRC loss of function, which produces the increased risk of chronic pancreatitis, have recently been elucidated [24]. Finally, exonic and intronic variants that are not generally tested for add to the genetic risks of chronic pancreatitis. Genetic testing is evolving, but at the current time these new insights have not translated into recommendations for routine genetic testing of patients with chronic pancreatitis.
AUTOIMMUNE PANCREATITIS Autoimmune pancreatitis comprises two variants. Type 1 is a systemic disease affecting pancreas, bile ducts, kidneys, salivary glands, retroperitoneum, and other organs. It is associated with elevations in serum levels of IgG4, and with infiltration of these affected organs by IgG4-bearing plasma cells. Type 2 affects only the pancreas, and is not associated with IgG4. Both types are steroid responsive, but relapses in Type 1 are common. Relapses generally require the use of immunosuppressives such as azathioprine [25], with agents such as rituximab used for failures of azathioprine [26]. The long-term outcome of this condition is not known, but exocrine and endocrine insufficiency can occur although pancreatic ductal stones and malignancy appear to be rare [27].
MANAGEMENT OF PAIN Pain in chronic pancreatitis is multifactorial with inflammatory and neuropathic components. Abnormalities in peripheral and central pain processing are Volume 30 Number 5 September 2014
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commonly identified [28–31] and these processes produce a sensitized pain state, in which therapy directed at the pancreas or pancreatic duct is often ineffective. A recent study from Bahuva et al. [32] documented again that the appearance of the pancreas on cross-sectional imaging and the severity of pain are often discordant, supporting the role of central mechanisms of pain in these patients. A similar study from Frokjaer et al. [33 ] confirmed these findings. Medical treatment options for painful chronic pancreatitis include avoidance of alcohol and smoking, pancreatic enzymes, pain medications, antioxidants, and adjunctive agents [10]. Pain management in the early stages may respond to nonnarcotic analgesics, but if the pain becomes more constant or debilitating, introduction of narcotic analgesics is appropriate [34]. Addiction and the abuse of narcotics do occur in these patients, and are particularly significant in patients with depression, higher pain intensity, and alcohol use [35]. Recent studies are mixed on the effect of antioxidants [10,36,37], but these agents may be effective in a subset of patients with preexisting nutritional deficiencies. One randomized study did document a modest effect of pregabalin as an adjunctive agent with narcotics [38]. Studies have not been performed on tricyclic antidepressants or selective serotonin reuptake inhibitor/norepinephrine and selective serotonin reuptake inhibitor agents, but they are commonly used as adjunctive agents as well [10]. If conservative medical treatment does not succeed, endoscopic treatment is pursued if the ductal anatomy is appropriate (i.e., a dilated main pancreatic duct with obstructing stone or stricture). He et al. [39 ] showed that use of the M-ANNHEIM classification system for chronic pancreatitis could improve time to diagnosis, allowing more time for early endoscopic intervention and improvement in pain relief and patient outcomes. Not all patients benefit from endoscopic therapy. In two randomized trials and in a systematic review published by D’Haese et al. [40], surgical treatment was seen to have better outcomes and is more long lasting compared with endoscopic intervention. Many patients still choose endoscopic therapy first, over a desire to avoid surgery. Endoscopic therapy, if undertaken, involves stenting of strictures and removal of pancreatic ductal stones. These stones are difficult to remove without extracorporeal or intraductal lithotripsy [41]. Long-term data on the use of lithotripsy were reported by Tandan et al. [42], who followed a large cohort (636) of patients with idiopathic (tropical) calcific pancreatitis who underwent extracorporeal shock wave lithotripsy (ESWL) followed by endoscopic retrograde cholangiopancreatography &
&
(ERCP). Absence of pain was seen in 60% of patients in long-term (up to 96 months) followup. Recurrence of calculi was seen in 22%. Quality of life improved substantially. The authors thus concluded that ESWL for large pancreatic duct calculi offers good results in patients with idiopathic calcific chronic pancreatitis on long-term followup [42]. Patients with a small pancreatic duct or diffuse punctate stones are not amenable to ESWL. Surgical therapy is usually recommended in patients who do not respond to medical or endoscopic therapy, those who have local complications such as biliary or duodenal obstruction, and in patients in whom malignancy cannot be excluded [10]. The optimal surgical procedure should manage pain, reduce opioid use, preserve as much as possible pancreatic exocrine and endocrine function, resolve local complications, and improve the quality of life [43 ]. Surgical approaches include lateral pancreaticojejunostomy or the modified Puestow procedure, the duodenum preserving pancreatic head resection procedures (Frey, Beger, or Berne) or the Whipple procedure. Bachmann and Tomkoetter [44] performed a randomized controlled trial comparing extended drainage procedure (Frey) with standard pylorus preserving pancreatoduodenectomy and found that organ-sparing procedure (Frey) showed better short-term results and a longer survival. Similarly, a study by Sudo et al. [45] from Japan showed that full-length lateral pancreaticojejunostomy was well tolerated, feasible, and effective for managing chronic pancreatitis. Thus organ-preserving surgery is preferred. After surgery, insulin independence and the use of PERT are associated with lower mortality [46]. Total pancreatectomy is rarely used for the treatment of chronic pancreatitis and is reserved for patients who failed previous surgical interventions, have severe pain with complete exocrine and endocrine pancreatic failure or as prophylactic procedure for pancreatic cancer in patients with hereditary pancreatitis or familial pancreatic cancer [43 ]. In recent years total pancreatectomy with islet cell autotransplantation (IAT) has been performed in patients with chronic pancreatitis. As patients get their own islet cells, it obviates the need for immunosuppressive therapy. Garcea et al. [47] observed that total pancreatectomy with IAT reduced pain, lowered insulin requirements, and conferred a surgical advantage over total pancreatectomy alone. TP-IAT is being utilized more frequently and at earlier stages of disease [48], although this approach is controversial. A recent systematic review noted reasonable pain relief in patients undergoing TP-IAT, with insulin independence of 46% at 5 years and 10% at 8 years after surgery [49].
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The optimal timing for surgical intervention in chronic pancreatitis is still debatable. Some advocate early surgery prior to the time that narcotic dependence develops. An open-label randomized controlled multicenter superiority trial by a Dutch group, the ESCAPE (Early Surgery versus Optimal Current Step-Up Practice for Chronic Pancreatitis trial) trial aims to compare early surgery versus the current step up treatment strategy in patients with chronic pancreatitis with dilated pancreatoduodenectomy and pain [50]. This trial may help to decide if early surgical intervention would lead to better long-term pain control and pancreatic function.
ENDOSCOPIC MANAGEMENT OF CHRONIC PANCREATITIS ASSOCIATED BILE DUCT STRICTURE OR PSEUDOCYST Endoscopic management of chronic pancreatitis is aimed at decreasing pain and treating associated complications, such as strictures (biliary and pancreatic), ductal leaks, intraductal calculi, or pseudocysts. Chronic pancreatitis related biliary strictures occur because of progressive fibrosis of pancreatic parenchyma and are more resistant to endoscopic dilation than other benign biliary strictures [51]. Wagh et al. [52] prospectively evaluated the efficacy of fully covered self-expandable metal stents as an alternative to plastic stenting in patients with biliary strictures, including those due to chronic pancreatitis. Short-term stricture resolution was seen in 96% of the patients, long-term success was seen in 83% of the patients. All of the failures were seen in patients with biliary strictures in the setting of chronic calcific pancreatitis. Similar findings were reported by Irani et al. [53]. These data underscore the recalcitrant nature of chronic pancreatitis associated biliary strictures, and imply that surgical biliary bypass is often preferable. Stenting is initially recommended in patients who present with jaundice or cholangitis as well as in patients unfit for surgery, or those who refuse surgery. Use of fully covered self-expandable metal stents by virtue of their larger diameter, better biliary drainage, and longer patency is a feasible alternative in treatment of common bile duct strictures related to chronic pancreatitis in nonsurgical patients [51]. Pseudocysts can be managed with endoscopic, surgical, or percutaneous methods. A recent randomized trial by Varadarajulu et al. noted similar efficacy and less cost for endoscopic drainage compared with surgical cystgastrostomy [54,55]. This trial suggests that endoscopic therapy should be the first-line treatment at centers with appropriate endoscopic expertise in EUS-guided drainage. 504
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CONCLUSION Literature from this year emphasized early diagnosis and intervention in treating patients with chronic pancreatitis. Patients with chronic pancreatitis are at risk of several nutrient deficiencies, which should be recognized and treated to improve outcomes. New guidelines for the diagnosis and management of pancreatogenic diabetes were published. Adjunctive treatments play a role in treatment of pain. Endoscopic treatment along with lithotripsy can be considered as an alternative to surgery in selected patients. Surgery is effective for treatment of pain and some complications, but endoscopic therapies are preferred for management of pseudocysts. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Stevens T, Lopez R, Adler DG, et al. Multicenter comparison of the interobserver agreement of standard EUS scoring and Rosemont classification scoring for diagnosis of chronic pancreatitis. Gastrointest Endosc 2010; 71:519–526. 2. Gardner TB, Taylor DJ, Gordon SR. Reported findings on endoscopic ultrasound examinations for chronic pancreatitis: toward establishing an endoscopic ultrasound quality benchmark. Pancreas 2014; 43:37–40. 3. Gheonea DI, Streba CT, Ciurea T, Saftoiu A. Quantitative low mechanical index contrast-enhanced endoscopic ultrasound for the differential diagnosis of pseudotumoral chronic pancreatitis and pancreatic cancer. BMC Gastroenterol 2013; 13:2. 4. Zhu M, Xu C, Wu Y, et al. Differentiation of pancreatic cancer and chronic pancreatitis using computer-aided diagnosis of endoscopic ultrasound (EUS) images: a diagnostic test. PLoS One 2013; 8:e63820. 5. Iglesias-Garcia J, Domı´nguez-Mun˜oz JE. Quantitative elastography associated with endoscopic ultrasound for the diagnosis of chronic pancreatitis. Endoscopy 2013; 45:781–788. 6. Janssen J, Papavassiliou I. Effect of aging and diffuse chronic pancreatitis on pancreas elasticity evaluated using semiquantitative EUS elastography. Ultraschall Med 2014; 35:253–258. 7. Hocke M, Ignee A, Dietrich CA. Advanced endosonographic diagnostic tools for discrimination of focal chronic pancreatitis and pancreatic carcinoma– elastography, contrast enhanced high mechanical index (CEHMI) and low mechanical index (CELMI) endosonography in direct comparison. Z Gastroenterol 2012; 50:199–203. 8. Sugita R, Furuta A, Yamakazi T, et al. Direct visualization of pancreatic juice & flow using unenhanced MRI with spin labeling can be an aid in diagnosing chronic pancreatitis. AJR Am J Ropentgenol 2014; 202:1027–1034. Spin labeling, a new technique, allows direct pancreatic juice visualization. 9. Cote GA, Smith J, Sherman S, Kelly K. Technologies for imaging the normal and diseased pancreas. Gastroenterology 2013; 144:1262–1271. 10. Forsmark CE. Management of chronic pancreatitis. Gastroenterology 2013; 144:1282–1291. 11. Ketwaroo G, Brown A, Young B, et al. Defining the accuracy of secretin pancreatic function testing in patients with suspected early chronic pancreatitis. Am J Gastroenterol 2013; 108:1360–1366. 12. Liao Z, Jin G, Cai D, et al. Guidelines: diagnosis and therapy for chronic pancreatitis. J Interv Gastroenterol 2013; 3:133–136. 13. Rasmussen HH, Irtun O, Olesen SS, et al. Nutrition in chronic pancreatitis. World J Gastroenterol 2013; 19:7267–7275.
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Chronic pancreatitis Gupte and Forsmark 14. Duggan SN, Smyth ND, O’Sullivan M, et al. The prevalence of malnutrition and fat-soluble vitamin deficiencies in chronic pancreatitis. Nutr Clin Pract 2014; 29:348–354. In chronic pancreatitis, malabsorption, pain and poor diet place patients at risk of malnutrition. In a prospective controlled cohort study, patients with chronic pancreatitis were noted to have lower muscle stores, strength, and abnormal vitamin levels. This highlights the importance to perform anthropometry and vitamin status assessment in patients with chronic pancreatitis. 15. Sikkens EC, Cahen DL, Koch AD, et al. The prevalence of fat-soluble vitamin deficiencies and a decreased bone mass in patients with chronic pancreatitis. Pancreatology 2013; 13:238–242. 16. Duggan SN, Smyth ND, Murphy A, et al. High prevalence of osteoporosis in patients with chronic pancreatitis: a systematic review and meta-analysis. Clin Gast Hepatol 2014; 12:219–228. 17. Bang UC, Benefield T, Bendtsen F, et al. The risk of fracture among patients with cirrhosis or chronic pancreatitis. Clin Gast Hepatol 2014; 12:320– 326. 18. Ewald N, Hardt PD. Diagnosis and treatment of diabetes mellitus in chronic & pancreatitis. World J Gastroenterol 2013; 19:7276–7281. The prevalence and importance of pancreatogenic diabetes are underestimated, and chronic pancreatitis as a potential cause of type 3 diabetes mellitus is underappreciated. In such patients, treating with appropriate enzyme replacement, preventing and treating fat-soluble vitamin deficiency, restoring fat hydrolysis, and incretin secretions are important considerations of medical therapy. 19. Rickels MR, Bellin M, Toledo FG, et al. Detection, evaluation and treatment of diabetes mellitus in chronic pancreatitis: recommendations from PancreasFest. Pancreatology 2013; 13:336–342. 20. Andersen DK, Andren-Sandberg A, Duell EJ, et al. Pancreatitis-diabetespancreatic cancer: summary of an NIDDK-NCI workshop. Pancreas 2013; 42:1227–1237. 21. Whitcomb DC. Genetic risk factors for pancreatic disorders. Gastroenterology 2013; 144:1292–1302. 22. Witt H, Beer S, Rosendahl J, et al. Variants in CPA1 are strongly associated with early onset chronic pancreatitis. Nat Genet 2013; 45:1216–1220. 23. Paliwal S, Bhaskar S, Mani KR, et al. Comprehensive screening of chymotrypsin C (CTRC) gene in tropical calcific pancreatitis identifies novel variants. Gut 2013; 62:1602–1606. 24. Beer S, Zhou J, Szabo A, et al. Comprehensive functional analysis of chymotrypsin C (CTRC) variants reveals distinct loss-of-function mechanisms associated with pancreatitis risk. Gut 2013; 62:1616–1624. 25. Kamisawa T, Chari ST, Lerch MM, et al. Recent advances in autoimmune pancreatitis: type 1 and type 2. Gut 2013; 62:1373–1380. 26. Hart PA, Topazian MD, Witzig TE, et al. Treatment of relapsing autoimmune pancreatitis with immunomodulators and rituximab: the Mayo experience. Gut 2013; 62:1607–1615. 27. Hart PA, Kamisawa T, Brugge WR, et al. Long-term outcomes of autoimmune pancreatitis: a multicenter, international analysis. Gut 2013; 62:1771–1776. 28. De Vries M, Wilder-Smith OH, Jongsma ML, et al. Altered resting state EEG in chronic pancreatitis patients: towards a marker for chronic pain. J Pain Res 2013; 25:815–824. 29. Bouwense SA, Ahmed Ali U, ten Broek RP, et al. Altered central pain processing after pancreatic surgery for chronic pancreatitis. Br J Surg 2013; 100:1797–1804. 30. Bouwense SA, Olesen SS, Drewes AM, et al. Is altered central pain processing related to disease stage in chronic pancreatitis patients with pain? An exploratory study. PLoS One 2013; 8:e55460. 31. Poulsen JL, Olesen SS, Malver LP, et al. Pain and chronic pancreatitis: a complex interplay of multiple mechanisms. World J Gastroenterol 2013; 19:7282–7291. 32. Bahuva R, Walsh RM, Kapural L, Stevens T. Morphologic abnormalities are poorly predictive of visceral pain in chronic pancreatitis. Pancreas 2013; 42:6–10. 33. Frokjaer JB, Olesen SS, Drewes AM. Fibrosis, atrophy, and ductal pathology & in chronic pancreatitis are associated with pancreatic function but independent of symptoms. Pancreas 2013; 42:1182–1187. In this Danish study, MRCP with diffusion weighted imaging was performed in patients with chronic pancreatitis and controls. Fibrosis, atrophy, and ductal pathology was noted in patients with chronic pancreatitis and these in turn were associated with Vit D, phosphate, hemoglobin, and glycated hemoglobin levels. However symptomatic chronic pancreatitis was noted to have a more complex pathophysiology independent of imaging pathology. 34. Enweluzo C, Tlhabano L. Pain management in chronic pancreatitis: taming the beast. Clin Exp Gastroenterol 2013; 6:167–171.
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35. Barth KS, Balliet W, P:elic CM, et al. Screening for current opiod misuse and associated risk factors among patients with chronic nonalcoholic pancreatitis pain. Pain MedD 2014 ; Doi: 10.1111/pme/12403 [Epub ahead of print] 36. Forsmark CE, Liddle RA. The challenging task of treating painful chronic pancreatitis. Gastroenterology 2012; 143:533–535. 37. Cai GH, Huang J, Zhao Y, et al. Antioxidant therapy for pain relief in patients with chronic pancreatitis: a systematic review and meta-analysis. Pain Physician 2013; 16:521–532. 38. Olesen SS, Bouwense SA, Wilder-Smith OH, et al. Pregabalin reduces pain in patients with chronic pancreatitis I a randomized, controlled trial. Gastroenterology 2011; 141:536–543. 39. He YX1, Xu HW, Sun XT, et al. Endoscopic management of early-stage & chronic pancreatitis based on M-ANNHEIM classification system: a prospective study. Pancreas 2014. [Epub ahead of print] M-ANNHEIM classification system was used to categorize patients with chronic pancreatitis. Patients receiving endoscopic treatment at early stage (1A) had more improvement in pain scores than those receiving treatment at later stages. Patients with stage 1A also had a higher incidence of post ERCP pancreatitis thus highlighting the importance of careful patient selection before undergoing therapeutic endoscopy. 40. D’Haese JG, Ceyhan GO, Demir IE, et al. Treatment options in painful chronic pancreatitis: a systematic review. HPB (Oxford) 2014; 16:512–521. 41. Kozarek R. Recent research on extracorporeal shock wave lithotripsy with ERCP for treatment of chronic calcific pancreatitis. Gastroenterol Hepatol (NY) 2012; 8:478–481. 42. Tandan M, Reddy DN, Talukdar R. Long-term clinical outcomes of extracorporeal shockwave lithotripsy in painful chronic calcific pancreatitis. Gastrointest Endosc 2013; 78:726–733. 43. Issa Y1, van Santvoort HC, van Goor H, et al. Surgical and endoscopic && treatment of pain in chronic pancreatitis: A multidisciplinary update. Dig Surg 2013; 30:35–50. Treatment of pain in chronic pancreatitis is challenging and evidence-based protocols are lacking. A plethora of medical, endoscopic, and surgical options are available but treatment needs to be individualized. This review highlights stepby-step approach toward treatment of pain in chronic pancreatitis with emphasis on ductal drainage and timing of surgical intervention. 44. Bachmann K, Tomkoetter L. Is the Whipple procedure harmful for long-term outcome in treatment of chronic pancreatitis? 15-years follow-up comparing the outcome after pylorus-preserving pancreatoduodenectomy and Frey procedure in chronic pancreatitis. Ann Surg 2013; 258:815–820. 45. Sudo T, Murakami Y, Uemura K, et al. Short- and long-term results of lateral pancreaticojejunostomy for chronic pancreatitis: a retrospective Japanese single-center study. J Hepatobiliary Pancreat Sci 2014; 21:426–432. 46. Winny M, Paroglou V, Bektas H, et al. Insulin independence and pancreatic enzyme replacement therapy are independent prognostic factors for long-term survival after operation for chronic pancreatitis. Surgery 2014; 155:271–279. 47. Garcea G, Pollard CA, Illouz S, et al. Patient satisfaction and cost-effectiveness following total pancreatectomy with islet cell transplantation for chronic pancreatic. Pancreas 2013; 42:322–328. 48. Bellin MD, Freeman ML, Gelrud A, et al. Total pancreatectomy and islet autotransplantation in chronic pancreatitis: recommendations from PancreasFest. Pancreatology 2014; 14:27–35. 49. Bramis K, Gordon-Weeks AN, Friend PJ, et al. Systematic review of total pancreatectomy and islet autotransplantation for chronic pancreatitis. Br J Surg 2012; 99:761–766. 50. Ahmed Ali U, Issa Y, Bruno MJ, et al. Early surgery versus optimal current stepup practice for chronic pancreatitis (ESCAPE): design and rationale of a randomized trial. BMC Gastroenterol 2013; 13:49. 51. Familiari P, Bosˇkoski I, Bove V, Costamagna G. ERCP for biliary strictures associated with chronic pancreatitis. Gastrointest Endosc Clin N Am 2013; 23:833–845. 52. Wagh MS, Chavalitdhamrong D, Moezardalan K, et al. Effectiveness and safety of endoscopic treatment of benign biliary strictures using a new fully covered self-expandable metal stent. Diagn Ther Endosc 2013; 183513. Doi: 10.1155/2013/183513. [Epub ahead of print] 53. Irani S, Baron TH, Akbar A, et al. Endoscopic treatment of benign biliary strictures using covered self-expandable metal stents (CSEMS). Dig Dis Sci 2014; 59:152–160. 54. Varadarajulu S, Bang JY, Sutton BS, et al. Equal efficacy of endoscopic and surgical cystgastrostomy for pancreatic pseudocyst drainage in a randomized trial. Gastroenterology 2013; 145:583–590. 55. Chauhan SS, Forsmark CE. Evidence-based treatment of pancreatic pseudocysts. Gastroenterology 2013; 145:511–513.
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